Research On Host Factors Underlying Clustering HBV Infected Families With Unfavorable Prognosis

With the introduction of hepatitis B virus (HBV) vaccination to national immunization programme, prevalence of HBsAg gradually decreased, however chronic HBV infection presents a significant national major public health problem. Hepatitis B virus infection presents a family-clustering style, household contacts in families with a member who was confirmed to have HBV infection are at high risk for development chronic infection; family-clustering HBV infection results in unfavorable prognosis, the relative risk of hepatocellular carcinoma was 50 among those with family history when compared with those without; carrier in clustering HBV infected family often link to unfavorable response when treated either with interferon or with nucleoside analogue; na?ve HBV family member has a unfavorable response to hepatitis B vaccine. To elucidate the underlying genetics and epigenetics mechanism for clustering HBV infected families with unfavorable prognosis (CHIFUP), we conduct the following research.After the collection of CHIFUP general and genetic information, we detected HBV markers, that is HBsAg, anti-HBs , HBeAg, anti-HBe, anti-HBc and HBV DNA, respectively. It was found that patients in family fit well with chronic HBV infection, most of those complete HBeAg/anti-HBe seroconversion before 35 years of age. Genetic epidemiology analysis unravel HBsAg, anti-HBc and HBV DNA positive rate among blood relatives was significantly higher when compared with non-blood relatives (spouses); HBsAg carrier rate decreased with the order of the first, second and third degree relatives. That provide new evidence for family-clustering HBV infection. Most important, we found some families present unfavorable prognosis (hepatocellular carcinoma). After pedigree analysis, we found HBV infection neither a autosomal dominant inheritance ,nor a autosomal recessive inheritance, nor sex linked dominant inheritance and nor sex linked recessive inheritance. We hold that HBV infection is a polygenic inheritance.To screen gene determinants in HBV infection, we constructed whole-genome expression profile by Affymetrix microarray U133 2.0 for 20 individuals in two HBV infected families. 55 genes out of 22,000 ESTs were identified differently. Among the 55 genes 14 showed increased expression and 41 showed decreased expression in CHB compared with those in normal controls. Most of the genes(57%) were involved in immune, inflammation, cell cycle, signaling transduction and apoptosis. 24 immune-related genes were identified differently in one family. Among the 24 genes 7 genes showed increased expression and 17 genes showed decreased expression in CHB compared with those in healthy spouses. 4 out of 7 up-regulated genes were mainly associated with adaptive immunity. Most of the down-regulated genes are associated with innate immunity. Those results suggest that defective innate immunity partly takes the responsibility for HBV infection.ClassⅡtransactivator (CⅡT A) is the major rate-limiting factor for both constitutive and interferon-γ-induced expression of MHC classⅡgene. PromoterⅣof CⅡTA homogeneously methylated in immune-tolerant phase patients from CHIFUP family, while homogeneously unmethylated in immune-tolerant. Immune tolerance of HBV persistent infection associated with methylation of CⅡTA-PⅣ, which probably due to that infected cells down regulate expression of MHC-Ⅱby methylation of CⅡTA-PⅣ.Based on this pilot study and findings, three projects, that is“positional cloning of host susceptible gene to HBV persistent infection”,“defected Nk cell function in HBV clustering infected families with prognosis”and“acetylation fo histones from hepatic infiltrated lymphocytes associated with HBV persistent infection”, are founded by NSFC and under execution.Conclusion: Based on genetics, molecular biology, epigenetics, bioinformatics research, we made conclusion as following: hepatitis B virus infection presents a family-clustering style, and family-clustering HBV infection results in unfavorable prognosis, which associated with host immune, inflammation, cell cycle, signaling transduction and apoptosis related gene differential expression. Innate immunity partly takes the responsibility for HBV infection. Immune tolerance of HBV persistent infection associated with methylation of CⅡTA-PⅣ.